INHIBITORS OF PRENYL TRANSFERASES

Description

Background of the Invention

[0001] The Ras family of proteins are important in the signal transduction pathway modulating cell growth. The protein is produced in the ribosome, released into the cytosol, and post- translationally modified. The first step in the series of post-translational modifications is the alkylation of Cys¹⁶⁸ with farnesyl or geranylgeranyl pyrophosphate in a reaction catalyzed by prenyl transferase enzymes such as farnesyl transferase and geranylgeranyl transferase (Hancock, JF, et al., Cell 57:1167-1177 (1989)). Subsequently, the three C-terminal amino acids are cleaved (Gutierrez, L., et al., EMBO J. 8:1093-1098 (1989)), and the terminal Cys is converted to a methyl ester (Clark, S., et al., Proc. Nat'l Acad. Sci. (USA) 85:4643-4647 (1988)). Some forms of Ras are also reversibly palmitoylated on cysteine residues immediately N-terminal to Cys¹⁶⁸ (Buss, JE, et al., Mol. Cell. Biol. 6:116-122 (1986)). It is believed that these modifications increase the hydrophobicity of the C-terminal region of Ras, causing it to localize at the surface of the cell membrane. Localization of Ras to the cell membrane is necessary for signal transduction (Willumsen, BM, et al., Science 310:583-586 (1984)).

[0002] Oncogenic forms of Ras are observed in a relatively large number of cancers including over 50 percent of colon cancers and over 90 percent of pancreatic cancers (Bos, JL, Cancer Research 49:4682-4689 (1989)). These observations suggest that intervention in the function of Ras mediated signal transduction may be useful in the treatment of cancer.

[0003] Previously, it has been shown that the C-terminal tetrapeptide of Ras is a "CAAX" motif (wherein C is cysteine, A is an aliphatic amino acid, and X is any amino acid). Tetrapeptides having this structure have been shown to be inhibitors of prenyl transferases (Reiss, et al., Cell 62:81-88 (1990)). Poor potency of these early farnesyl transferase inhibitors has prompted the search for new inhibitors with more favorable pharmacokinetic behavior (James, GL, et al., Science 260:1937-1942 (1993); Kohl, NE, et al., Proc. Nat'l Acad. Sci. USA 91:9141-9145 (1994); deSolms, SJ, et al., J. Med. Chem. 38:3967-3971 (1995); Nagasu, T, et al., Cancer Research 55:5310-5314 (1995); Lerner, EC, et al., J. Biol. Chem. 270:26802-26806 (1995); Lerner, EC, et al., J. Biol. Chem. 270:26770 (1995); and James, et al., Proc. Natl. Acad. Sci. USA 93:4454 (1996)).

[0004] Recently, it has been shown that a prenyl transferase inhibitor can block growth of Ras-dependent tumors in nude mice (Kohl, NE, et al., Proc. Nat'l Acad. Sci. USA 91:9141-9145 (1994)). In addition, it has been shown that over 70 percent of a large sampling of tumor cell lines are inhibited by prenyl transferase inhibitors with selectivity over non-transformed epithelial cells (Sepp-Lorenzino, I, et al., Cancer Research, 55:5302-5309 (1995)).

Summary of the Invention

[0005] In one aspect, the invention features a compound of formula I or formula II

wherein
R₁ is H or NR₂₀R₂₁;
R₂ is (CH₂)_mSR₂₂, (CH₂)_mSSR₂₂, substituted or unsubstituted heterocycle, or substituted or unsubstituted heterocycle lower alkyl, where m is 1-6 and the substituent is lower alkyl, lower alkenyl, aryl, or aryl lower alkyl;
each of R₃ and R₇, independently, is CH₂ or C(O);
each of R₄ and R₁₅, independently, is H or lower alkyl;
each of R₅ and R₁₆, independently, is H or a substituted or unsubstituted moiety selected from lower alkyl, thio lower alkyl, lower alkenyl, thio lower alkenyl, cycloalkyl, cycloalkyl lower alkyl, aryl, and aryl lower alkyl, where the substituent is lower alkyl, hydroxy, halo, C(O)KR₂₃R₂₄, or COOH;
each of R₆, R₈, R₉, R₁₁, R₁₂, R₁₃, and R₁₇, independently, is H or a substituted or unsubstituted moiety selected from lower alkyl, lower alkenyl, thio lower alkyl, cycloalkyl, aryl, and aryl lower alkyl, where the substituent is lower alkyl, halo, hydroxy, C(O)NR₂₅R₂₆, or COOH;
R₁₀ is S, SO, or SO₂;
R₁₈ is COOR₂₇ or C(O)NR₂₈R₂₉, or, together with R₁₆, forms -COOCH₂CH₂-.

[0006] R₁₉ is a substituted (with one or more substituents; same below) or unsubstituted moiety selected from lower alkyl, lower alkenyl, aryl, and aryl lower alkyl, where the substituent is lower alkyl (e.g., an alkyl group can also be deemed as a substituent too), halo, or alkoxy; and
each of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, and R₂₉, independently, is H or lower alkyl;
provided that if R₂ is (CH₂)_mSH and R₅ is thio lower alkyl, the free thio groups of R₂ and R₅ can form a disulfide bond; or a pharmaceutically acceptable salt thereof.

[0007] In one embodiment, the compound is of formula I where R₂ is (CH₂)_mSR₂₂, heterocycle, or heterocycle lower alkyl; each of R₄ and R₁₅, independently, is H; R₅ is lower alkyl; R₆ is H; each of R₈, R₉, R₁₁, and R₁₂, independently, is H or lower alkyl; R₁₀ is S; R₁₃ is H; R₁₆ is lower alkyl or substituted thio lower alkyl wherein the substituent is lower alkyl; and R₁₇ is H. In this embodiment, R₁ can be NR₂₀R₂₁ (e.g., NH₂); R₂ can be (CH₂)_mSR₂₂ (e.g., CH₂SH); R₃ can be CH₂; each of R₈ and R₉, independently, can be H; and R₁₈ can be COOR₂₇; furthermore, R₅ can be CH(CH₃)(CH₂CH₃), (CH₂)₃CH₃, CH (CH₃)₂, or C(CH₃)₃; each of R₁₁ and R₁₂, independently, can be CH₃; R₁₆ can be (CH₂)₂ SCH₃ or CH₂ CH (CH₃)₂ ; and R₁₈ can be COOH or COOCH₃. In the same embodiment, R₁ can be H; R₂ can be heterocycle or heterocycle lower alkyl; R₃ can be CH₂; each of R₈ and R₉, independently, can be H; and R₁₈ can be COOR₂₇ where R₂₇ is H or lower alkyl; furthermore, R₂ can be imidazolyl or imidazolyl lower alkyl; R₅ can be CH(CH₃) (CH₂CH₃), CH(CH₃)₂, or C(CH₃)₃; each of R₁₁ and R₁₂, independently, can be CH₃; R₁₆ can be (CH₂)₂SCH₃, (CH₂)₃CH₃, or CH₂CH(CH₃)₂; and R₁₈ can be COOH or COOCH₃.

[0008] In another embodiment, the compound is of formula II where R₂ is (CH₂)_mSR₂₀, heterocycle, or heterocycle lower alkyl; each of R₈, R₉, R₁₁, and R₁₂, independently, is H or lower alkyl; R₁₀ is S; R₁₃ is H; and R₁₅ is H. In this embodiment, R₁ can be NR₂₀R₂₁; R₂ can be (CH₂)_mSR₂₂; R₃ can be CH₂; each of R₈ and R₉, independently, can be H; and R₁₉ can be substituted or unsubstituted aryl lower alkyl wherein the substituent is halo or lower alkyl; furthermore, R₁ can be NH₂; R₂ can be CH₂SH; each of R₁₁ and R₁₂ independently, can be CH₃; and R₁₉ is 2,3-dichlorobenzyl or 1-naphthyl-methyl. In the same embodiment, R₁ can be H; R₂ can be heterocycle, or heterocycle lower alkyl; R₃ can be CH₂; each of R₈ and R₉, independently, can be H; and R₁₉can be substituted or unsubstituted aryl lower alkyl wherein the substituent is halo or lower alkyl; furhtermoe, R₂ can be imidazolyl or imidazolyl lower alkyl; each of R₁₁ and R₁₂, independently, can be CH₃; and R₁₉ can be 2,3-dichlorobenzyl or 1-napthylmethyl.

[0009] Examples of the present invention include the following:







































and

[0010] In another aspect, the invention features a dimeric compound consisting of a first moiety and a second moiety, wherein each of the first and second moieties, independently, is of formula I or formula II shown above except that each R₂ of the first moiety and R₂ of the second moiety, independently, are -(CH₂)_mS- and form a disulfide bond; or a pharmaceutically acceptable salt thereof. The first and second moieties can be identical or different. Indeed, R₂ of the first moiety and R₂ of the second moiety can also be identical or different. An example of such a dimeric compound is shown below:

[0011] The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. For simplicity, where no specific configuration is depicted in the structural formulae, it is understood that all enantiometric forms and mixtures thereof are represented.

[0012] As used herein, "lower alkyl" is intended to include saturated aliphatic hydrocarbon groups having 1-6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and the like. "Lower alkenyl" groups include those groups having 2-6 carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, and the like. "Lower alkoxy" groups include those groups having 1-6 carbons. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and the like. All alkyl, alkenyl, and alkoxy groups may be branched or straight chained, but are noncyclic. The term "cycloalkyl" means a 3-7 carbon ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "halo" means chloro, bromo, iodo, or fluoro. The terms "heterocycle lower alkyl," "thio lower alkyl," "thio lower alkenyl," "aryl lower alkyl," and "hydroxy lower alkyl," are substituted, respectively, with one to three heterocycle, thio, thio, aryl, and hydroxy groups.

[0013] As used herein, "aryl" is intended to include any stable monocyclic, bicyclic, or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl, and the like.

[0014] The term heterocycle, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11 to 15-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thiazolidinyl, thienofuryl, thienothienyl, thienyl, and the like.

[0015] When a group is substituted, it may be substituted one to four times. The various substituents may be attached to carbon atoms or to heteroatoms (e.g., S, N, or O).

[0016] The compounds of this invention can be provided in the form of pharmaceutically acceptable salts. Acceptable salts include, but are not limited to acid addition salts of inorganic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate, and stearate. Also within the scope of the present invention, where applicable, are salts formed from bases such as sodium or potassium hydroxide. For further examples of pharmaceutically acceptable salts see, "Pharmaceutical Salts," J. Pharm. Sci. 66:1 (1977).

[0017] In a still further aspect, the invention features a method of inhibiting prenyl transferases (e.g., farnesyl transferase or geranylgeranyl transferase) in a subject, e.g., a mammal such as a human, by administering to the subject a therapeutically effective amount of a compound of formula I or formula II. In particular, the present invention also covers a method of treating restenosis or tissue proliferative diseases (i.e., tumor) in a subject by administering to the subject a therapeutically effective amount of a compound or its salt. Examples of tissue proliferative disease include both those associated with benign (e.g., non-malignant) cell proliferation such as fibrosis, benign prostatic hyperplasia, atherosclerosis, and restenosis, and those associated with malignant cell proliferation, such as cancer (e.g., ras mutant tumors). Examples of treatable tumors include breast, colon, pancreas, prostate, lung, ovarian, epidermal, and hematopoietic cancers (Sepp-Lorenzino, I, et al., Cancer Research 55:5302 (1995)).

[0018] A therapeutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier substance (e.g., magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle) together form a pharmaceutical composition (e.g., a pill, tablet, capsule, or liquid) for administration (e.g., orally, intravenously, transdermally, or subcutaneously) to a subject in need of the compound. The pill, tablet, or capsule can be coated with a substance capable of protecting the composition from the gastric acid or intestinal enzymes in the subject's stomach for a period of time sufficient to allow the composition to pass undigested into the subject's small intestine.

[0019] The dose of a compound of the present invention for treating the above-mentioned diseases or disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such an amount of the compound as determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount."

[0020] Also contemplated within the scope of the invention are pharmaceutical preparations of compounds of formula I and formula II, methods of preparing the compounds of formula I or formula II, and the novel chemical intermediates used in these syntheses as described herein.

[0021] Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.

Detailed Description of the Invention

[0022] It is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.

[0024] The following is a description of the synthesis of Compounds 1 to 12. Other compounds of the invention can be prepared in an analogous manner by a person of ordinary skill in the art.

[0025] The compounds of this invention were prepared by using standard solution phase peptide synthesis methodologies as well as other standard manipulations such as ester hydrolysis and reductive akylation of an amine by an aldehyde, e.g., as described in Greenstein, et al., Chemistry of the Amino Acids, Vols. 1-3 (J. Wiley, New York (1961)); and M. Bodanszky, et al.., The Practice of Peptide Synthesis (Springer-Verlag, 1984)). For amide formation reactions, EDC/HOBt or HBTU/DIEA/DMF was used as the coupling agent. Deprotection of the protecting groups was done by using TFA/DCM. The reducing agent used in the reductive alkylation of an amine was sodium cyanoborohydride. The final products were purified by using preparative HPLC and analyzed by ¹H NMR or mass spectroscopy.

EXAMPLE 1: N-[N'-[2(S)-(2(R)-Amino-3-mercaptopropylamine)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine (Compound 1)

(a) N-α-(tert-Butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxylic acid:

[0026] A solution of L-5,5-dimethylthiazolidine-4-carboxylic acid (2.5 g, 15.5 mmol) in water (10 mL), dioxane (20 mL), and 2N NaOH (7.8 mL) was stirred and cooled in an ice-water bath. Di-tert-butyl dicarbonate (3.72 g, 17.1 mmol) was added and stirring was continued at room temperature overnight. The solution was concentrated in vacuo to about 25 mL and ethyl acetate (EtOAc; 30 mL) was added. The pH of the solution was adjusted to 2 at 0°C by addition of 2N HC1. The organic layer was separated, and the aqueous layer was extracted with EtOAc (20 mL). The two organic layers were combined, washed with water (2 times), dried over anhydrous MgSO₄, filtered, and evaporated in vacuo. The title compound, as a white solid (3.60 g; Yield: 89%), was obtained, and it was used in the next reaction without further purification. ¹H NMR (300 MHz, CDCl₃) δ 4.68 (m, 2H), 4.39 (s, 1H) 4.23 (s, 1H), 1.60-1.40 (m, 15H).

(b) N-[(tert-Butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxylic]-L-methionine methyl ester:

[0027] A solution of N-(tert-butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxylic acid (1.00 g, 3.83 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 0.734 g; 3.83 mmol), 1-hydroxybenzotriazole (HOBt; 0.517 g; 3.83 mmol), and diisopropylethylamine (DIEA; 0.495 g; 3.83 mmol) in dichloromethane (DCM; 20 mL) was stirred at 0°C for 10 minutes. To this solution was added methionine methyl ester hydrochloride (0.765 g, 3.83 mmol). The mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with 5% citric acid (2 times), 5% Na₂CO₃ (2 times), and brine (2 times), dried over anhydrous MgSO₄, and filtered. The residue obtained after concentration was further purified by column chromatography on silica, eluting with hexanes/EtOAc (2:1). The title compound, as a white solid (1.09 g; Yield: 70%), was obtained. ¹H NMR (300 MHz, CHCl₃) δ 6.67 (d, 1H), 4.78-4.60 (m, 3H), 4.11 (s, 1H), 3.75 (s, 3H), 2.55 (m, 2H), 2.24-2.00 (m, 5H), 1.56-1.40 (m, 15H).

(c) N-α-(tert-Butoxycarbonyl)-N-methoxy-N-methyl-L-isoleucinamide

[0028] A solution of N-α-(tert-butoxycarbonyl)-isoleucine (8.00 g, 33.3 mmol), O-benzotriazole-N,H,N',N'-tetramethyl-uronium-hexafluorophosphate (HBTU; 12.63 g; 33.3 mmol), DIEA (17.21g, 133.2 mmol) in dimethylformamide (DMF, 35 mL) was stirred at room temperature for 2 minutes. To this solution was added N,O-dimethylhydroxylamine hydrochloride (3.25 g, 33.3 mmol), and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc and washed with 5% citric acid (2 times), 5% Na₂CO₃ (2 times) and brine (2 times), dried over anhydrous MgSO₄, and filtered. The residue obtained after concentration was further purified by column chromatography on silica, eluting with EtOAc/hexanes (1:1). 8.5 g (Yield: 90%) of the title compound was obtained. ¹H NMR (300 MHz, CDCl₃) δ 5.12 (d, 1H), 4.62 (m, 1H), 3.79 (s, 3H), 3.23 (s, 3H), 1.72 (m, 1H), 1.58 (m, 1H), 1.45 (s, 9H), 1.30-1.05 (m, 1H), 1.00-0.85 (m, 6H).

(d) N-α-(tert-Butoxycarbonyl)-L-isoleucinal

[0029] LiAlH₄ (0.20 g, 5.25 mmol) in 20 mL of anhydrous ether was stirred at room temperature for 30 minutes. The suspension was cooled to -45 °C, and a solution of N-α-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-isoleucinamide (1.10 g, 3.89 mmol) in 6 mL of tetrahydrofuran (THF) was added dropwise to the suspension. The mixture was warmed to 0°C and stirred for 2 hours. The mixture was then cooled to -45°C. To this solution was slowly added a solution of KHSO₄ (1.17 g) in H₂O (10 mL). The resulting mixture was filtered through Celite. The filtrate was washed with 5% citric acid (2 times) and brine (2 times), dried over anhydrous MgSO₄, filtered, and concentrated to dryness. 0.70 g of the title compound, as a colorless oil, was obtained and was immediately used in the next step without further purification.

(e) N-[N'-[2(S)-(tert-Butoxycarbonylamino)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester

[0030] N-[(tert-Butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxyl]-L-methionine methyl ester (1.09 g, 2.68 mmol) was dissolved in a mixture of TFA (15 mL) and DCM (15 mL) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo. The resulting residue and N-α-(tert-butoxycarbonyl)-L-isoleucinal (0.70 g, 3.25 mmol) were dissolved in a mixture of methanol (MeOH; 30 mL) and acetic acid (0.6 mL). To this solution was added in portions sodium cyanoborohydride (0.204 g, 3.25 mmol) over a period of 30 minutes. MeOH was removed in vacuo. To the rest of the solution was added EtOAc and saturated NaHCO₃. The organic layer was separated and washed with saturated NaHCO₃ (1 time), water (1 time) and brine (1 time), dried over anhydrous MgSO₄, filtered, and concentrated. The residue obtained was further purified by column chromatography on silica, eluting with EtOAc/hexanes (1:2). 1.06 g (Yield: 78%) of the title compound was obtained. ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, 1H), 4.68 (m, 1H), 4.53 (s, 2H), 3.90 (m, 1H), 3.79 (s, 1H), 3.75 (s, 3H), 3.42 (s, 1H), 2.95 (dd, 1H), 2.78 (dd, 1H), 2.50-2.70 (m, 2H), 2.22 (m, 2H), 2.13 (s, 3H), 1.60-1.40 (m, 12H), 1.36 (m, 2H), 1.38 (m, 2H), 0.92 (m, 9H); mass spectroscopy (electron spray) ((MS(ES)): 505.4, Calculated molecular weight (Calc. MW) = 505.7.

(f) N-α-(tert-Butoxycarbonyl)-S-(triphenylmethyl)-L-cysteinal

[0031] The title compound was synthesized starting with N-α-(tert-butoxycarbonyl)-S-(triphenylmethyl)-L-cysteine by using the same procedure described in the synthesis of N-α-(tert-butoxycarbonyl)-L-isoleucinal.

(g) N-[N'-[2(S)-(2(R)-(tert-Butoxycarbonylamino)-3-triphenylmethyl-mercaptopropylamine)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester

[0032] N-[N'-[2(S)-(tert-Butoxycarbonylamino)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester (1.06 g, 2.10 mmol) was dissolved in a mixture of trifluoroacetic acid (TFA; 15 mL) and DCM (15 mL) and stirred for 30 minutes at room temperature. The solution was concentrated in vacuo. The residue obtained and N-α-(tert -butoxycarbonyl)-S-(triphenylmethyl)-L-cysteinal (1.10 g, 2.46 mmol) were dissolved in a mixture of MeOH (15 mL) and HOAc (0.3 mL). To this was added in portions sodium cyanoborohydride (0.158 g, 2.52 mmol) over a period of 30 minutes. The mixture was stirred at room temperature overnight. 5 mL of saturated NaHCO₃ was added, and MeOH was removed in vacuo. To the rest of the solution was added EtOAc and saturated NaHCO₃. The organic layer was separated and washed with saturated NaHCO₃ (1 time) and brine (2 times), dried over anhydrous MgSO₄, and filtered. Concentration in vacuo gave the title compound, which was used directly in the next step without further purification. MS(ES): 836.5, Calc. MW=836.8.

(h) N-[N'-[2(S)-(2(R)-Amino-3-mercaptopropylamine)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine

[0033] N-[N'-[2(S)-(2(R)-(tert-Butoxycarbonylamino)-3-triphenylmethylmercaptopropylamine)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester (0.50 g, 0.42 mmol) was dissolved in a mixture of MeOH (16 mL) and 5 N NaOH (4 mL) at 0°C and stirred for 3 hours. The solution was neutralized to pH 7 by addition of 2N HCL. MeOH was removed in vacuo and EtOAc was added. The mixture was cooled to 0°C, and the aqueous layer was acidified to pH 2 by adding 2N HCl. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The organic layers were pooled, washed with brine (1 time), dried over anhydrous MgSO₄, and filtered. The residue obtained after concentration in vacuo was dissolved in a mixture of trifluoroacetic acid (TFA; 6 mL), DCM (6 mL), and triethylsilane (0.6 mL). The solution was stirred at room temperature for 40 minutes. The residue after concentration in vacuo was partitioned between ether and 0.1% TFA aqueous solution. The aqueous layer was separated, purified on a preparative high performance liquid chromatography (HPLC) eluting with 0.1% TFA in H₂O/CH₃CN buffer, and lyophilized to give the title compound. MS(ES): 480.3, Calc. MW=480.8

EXAMPLE 2: N-[N'-[2(S)-(2(R)-Amino-3-mercaptopropylamine)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester (Compound 2)

[0034] N-[N'-[2(S)-(2(R)-(tert-Butoxycarbonylamino)-3-triphenylmethylmercaptopropylamine)-3(S)-methylpentyl]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester (0.60 g, 0.718 mmol; Example 1(g)) was dissolved in a mixture of TFA (10 mL), DCM (10 mL), and triethylsilane (1 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated in vacuo. The residue was partitioned between 1% TFA aqueous solution and ether. The aqueous layer was separated, purified by HPLC, and lyophilized to give the title compound. MS(ES): 494.3, Calc. MW=494.8.

EXAMPLE 3: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine (Compound 3)

(a) N-[N'[(tert-Butoxycarbonyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]methionine methyl ester

[0035] N-[(tert-Butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester (1.63 g; 4.01 mmol; Example 1(b)) was dissolved in a mixture of TFA (5 mL) and DCM (5 mL) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo. The residue was dissolved in toluene, and the solution was condensed in vacuo. This procedure was repeated three times and a white foam was obtained.

[0036] A solution of N-α-(tert-butoxycarbonyl)-tert-leucine (1.0 g, 4.01 mmol), EDC (0.769 g, 4.01 mmol), HOBt (0.650 g, 4.81 mmol), and DIEA (0.570 g, 4.41 mmol) in DCM (15 mL) was stirred at room temperature for 10 minutes. To it was added the above white foam. The mixture was stirred overnight. The solution was diluted with DCM (15 mL) and washed with 5% NaHCO₃ (2 times), 5% citric acid (2 times), and brine (2 times), dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography, eluting with hexanes : EtOAc (2:1) and hexanes:EtOAc (1:1). 0.63 g of the title compound was obtained (Yield: 30%). ¹H NMR (300 MHz, CDCl₃) δ 6.48 (d, 1H), 5.25 (d, 1H), 5.12 (d, 1H), 4.95-4.62 (m, 2H), 4.43-4.30 (m, 2H), 3.77 (s, 3H), 2.58 (m, 2H), 2.21, (m, 1H), 2.11 (s, 3H), 2.04 (m, 1H), 1.55-1.33 (m, 12H), 1.12-0.94 (m, 12H).

(b) N-[N'-[N"-(2(R)-(tert-Butoxycarbonylamino)-3-triphenylmethyl-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester

[0037] 0.6 g (1.15 mmol) of N-[N'-[tert-butoxycarbonyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester was dissolved in a mixture of TFA (5 mL), DCM (5 mL) and triethylsilane (Et₃SiH) (1 mL) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo. The residue was dissolved in toluene, and the solution was condensed to dryness. This procedure was repeated until a white foam was obtained (4 times). This foam and 0.5 g (1.12 mmol) of N-α-(tert-butoxycarbonyl)-S-(triphenylmethyl)-L-cysteinal (Example 1(f)) were dissolved in 4 mL of methanol and 0.2 mL of acetic acid. To this mixture was added NaBH₃CN (72 mg, 1.15 mmol), and it was stirred for 30 minutes. 0.5 g (1.12 mmol) of N-α-(tert-butoxycarbonyl)-S-(triphenylmethyl)-L-cysteinal and 72 mg (1.15 mmol) of NaBH₃CN were added. The reaction mixture was stirred for 30 minutes. 0.5 g (1.12 mmol) of N-α-(tert-butoxycarbonyl)-S-(triphenylmethyl)-L-cysteinal and 72 mg (1.15 mL) of NaBH₃CN were then added followed by addition of 0.1 mL of acetic acid. The solution was stirred overnight and concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO₃ (2 times) and brine (2 times), dried over anhydrous MgSO₄, filtered, and condensed in vacuo. The residue was purified by using column chromatography (silica), eluting with EtOAc:hexanes (1:2) and EtOAc:hexanes (1:1). 930 mg (Yield: 95%) of the title compound, as a white solid, was obtained. MS(ES) : 850.5 Calc. MW = 850.8

(c) N-[N'-[N"(2(R)-Amino-3-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine

[0038] 230 mg (0.27 mmol) of N-[N'-[N"-(2(R)-(tert-butoxycarbonylamino)-3-triphenylmethyl-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester was dissolved in 2 mL of methanol at 0°C. To it was added 0.4 mL of 1 N KOH solution. The white precipitate was dissolved by addition of 0.8 mL of THF. The mixture was warmed to room temperature and stirred for 1.5 hours. To the solution was added 2 N Hcl at 0°C until the pH was about 2. The solution was diluted to 25 mL by addition of EtOAc and then 10 mL of brine was added. The organic layer was separated, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to give a white solid (220 mg). The white solid was dissolved in a mixture of 5 mL of DCM and 1 mL of triethylsaline (Et₃SiH). To it was added 5 mL of TFA, and the solution was stirred for 40 minutes. The solution was concentrated in vacuo. The white solid was triturated with hexanes and then dissolved in 0.1 % TFA aqueous solution. It was purified on a preparative HPLC and lyophilization gave the title compound (47 mg; Yield: 36 %). ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, 1H), 5.02 (d, 1H), 4.74 (d, 1H), 4.66 (m, 1H), 4.53 (s, 1H), 4.47 (m, 1H), 3.30 (m, 2H), 2.77 (m, 2H), 2.58 (m, 1H), 2.51 (m, 4H), 2.03 (m, 4H), 1.82 (m, 1H) 1.54 (s, 2H), 1.38 (s, 3H), 1.03 - 0.88 (m, 12H); MS (ES): 494.2, Calc. MW=494.7

EXAMPLE 4: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine methyl ester (Compound 4)

[0039] 660 mg (0.776 mmol) of N-[N'-[N"-(2(R)-(tert-butoxycarbonyl-amino)-3-triphenylmethyl-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazplidine-4-carboxyl]-methionine methyl ester (Example 3(b)) was dissolved in a mixture of DCM (5 mL) and Et₃SiH (1 mL). To it was added 5 mL of TFA. The mixture was stirred at room temperature for 0.5 hours. The solution was concentrated in vacuo. The residue was triturated with hexanes and then dissolved in 0.1 % TFA aqueous solution. It was purified by a preparative HPLC, eluting with a gradient (buffer A: 0.1 % TFA in H₂O, buffer B: 0.1 % TFA in CH₃CN). Lyophilization gave the title compound as a white solid (310 mg; Yield; 78%). MS (ES): 508.3, Calc. MW = 508.8.

EXAMPLE 5: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-leucine (Compound 5)

[0040] The title compound was synthesized by using an analogus procedure described in the synthesis of Example 3. MS(ES): 476.2, Calc. MW = 476.3.

EXAMPLE 6: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-tert-leucine]-L-5,5-dimethylthiazolidine-4-carboxyl]-leucine-methyl ester

[0041] The title compound was synthesized by using an analogous procedure described in the synthesis of Example 4. MS(ES):490.3, Calc. MW = 490.7.

EXAMPLE 7: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-valine]-L-5,5-dimethylthiazolidine-4-carboxyl]-leucine (Compound 7)

[0042] The title compound was synthesized by using an analogous procedure described in the synthesis of Example 3. MS(ES): 462.4, Calc. MW = 462.7.

EXAMPLE 8: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-valine]-L-5,5-dimethylthiazolidine-4-carboxyl]-leucine-methyl ester (Compound 8)

[0043] The title compound was synthesized by using an analogous procedure described in the synthesis of Example 4. MS(ES): 476.3, Calc. MW = 476.7.

EXAMPLE 9: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-valine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine (Compound 9)

[0044] The title compound was synthesized by using an analogous procedure described in the synthesis of Example 3. MS(ES): 480.3, Calc. MW = 480.7.

EXAMPLE 10: N-[N'-[N"-(2(R)-Amino-3-mercaptopropyl)-valine]-L-5,5-dimethylthiazolidine-4-carboxyl]-methionine-methyl ester (Compound 10)

[0045] The title compound was synthesized by using an analogous procedure described in the synthesis of Example 4. MS(ES): 494.3, Calc. MW = 494.8.

EXAMPLE 11: [N-(2(R)-Amino-3-mercaptopropyl)-L-5,5-dimethylthiazolidine-4-carboxyl]-2,3-dichlorobenzamide (Compound 11)

(a) [(tert-Butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxyl]-2,3-dichlorobenzamide

[0046] A solution of N-α-(tert-butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxylic acid (0.65 g, 2.50 mmol; Example 1(a)), HBTU (0.948 g, 2.50 mmol), and DIEA (1.3 g, 10 mmol) in DMF (25 mL) was stirred at room temperature for 3 minutes. To it was added 2, 3-dichlorobenzylamine (0.44 g, 2.50 mmol). The mixture was stirred overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc, washed with 5% NaHCO₃ (2 times), 5% citric acid (2 times), and brine (2 times), dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The title compound (0.83 g; Yield: 79%) was obtained after chromatography (silica) with EtOAc:hexanes (1:2). ¹H NMR (300 MHz, CDCl₃) δ 7.40 (m, 2H), 7.18 (m, 1H), 6.55 (bs, 1H), 4.65 (m, 3H), 4.52 (m, 1H), 4.07 (s, 1H), 1.58 (s, 3H), 1.20, (m, 12H).

(b) [N-(2(R)-Amino-3-mercaptopropyl)-L-5,5-dimethylthiazolidine-4-carboxyl]-2,3-dichlorobenzamide

[0047] [(tert-Butoxycarbonyl)-L-5,5-dimethylthiazolidine-4-carboxyl]-2,3-dischlorobenzamide (0.419 g, 1 mmol) was dissolved in 10 mL of 50 % TFA in DCM. The mixture was stirred at room temperature for 0.5 hours. TFA and the solvent were removed in vacuo. The residue and N-α-(tert-butoxycarbonyl)-S-(triphenylmethyl)-L-cysteinal (2 mmol; Example 1(f)) were dissolved in MeOH (10 mL) and HOAc (0.2 mL). To it was added in portions sodium cyanoborohydride (94 mg, 1.5 mmol). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo, and the residue was dissolved in EtOAc. The solution was washed with 5% NaHCO₃ (2 times), 5% citric acid (2 times) and brine (2 times), dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in 15 mL of DCM and 2 mL of triisopropylsilane. To the solution was added 10 mL of TFA. The reaction mixture was stirred at room temperature for 0.5 hours. The solution was condensed in vacuo, and the resulting residue was partitioned between 0.1% TFA aqueous solution and EtOAc. The organic layer was concentrated in vacuo. The residue was triturated with hexanes and then purified by HPLC. Lyophilization gave the title compound (339 mg; Yield: 83%). MS (ES): 407.0, Calc. MW = 407.4. ¹H NMR (300 MHz, CDCl₃) δ 8.21 (bs, 2H), 7.61 (t, 1H), 7.41 (dd, 1H), 7.27 (dd, 1H), 7.19 (dd, 1H), 4.55 (d, 2H), 4.43 (d, 1H), 3.88, (d, 1H), 3.28 (s, 1H), 3.22 (m, 1H), 3.10 (m, 2H), 2.79 (m, 2H), 1.73 (bs, 1H), 1.57 (s, 3H), 1.38 (s, 3H).

EXAMPLE 12: [N-(2(R)-Amino-3-mercaptopropyl)-L-5,5-dimethylthiazolidine-4-carboxyl]-naphthylmethyl amide (Compound 12)

[0048] The title compound was synthesized by using an analogous procedure to Example 11. MS(ES): 389.1, Calc. MW = 389.6 ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, 1H), 7.90 (m, 1H), 7.82 (d, 1H), 7.61-7.41 (m, 5H), 5.22 (dd, 1H), 4.63 (dd, 1H), 4.39 (d, 1H), 3.78 (d, 1H), 3.24 (s, 1H), 2.97 (m, 2H), 2.76 (m, 1H), 2.48 (m, 2H), 1.57 (s, 3H), 1.40 (s, 3H), 1.28 (m, 1H).

Other Embodiments

[0049] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the claims.

Claims

1. A compound of formula I or formula II

wherein
R₁ i s H or NR₂₀R₂₁;
R₂ is (CH₂)_mSR₂₂, (CH₂)_mSSR₂₂, substituted or unsubstituted heterocycle, or substituted or unsubstituted heterocycle (C₁-C₆) alkyl, where m is 1-6 and said substituent is C₁-C₆) alkyl, C₁-C₆) alkenyl, aryl, or aryl C₁-C₆) alkyl;
each of R₃ and R₇, independently, is CH₂ or C (O) ;
each of R₄ and R₁₅, independently, is H or C₁-C₆) alkyl;
each of R₅ and R₁₆, independently, is H or a substituted or unsubstituted moiety selected from C₁-C₆) alkyl, thio C₁-C₆) alkyl, C₁-C₆) alkenyl, thio C₁-C₆) alkenyl, cycloalkyl, cycloalkyl C₁-C₆) alkyl, aryl, and aryl C₁-C₆) alkyl, where said substituent is C₁-C₆) alkyl, hydroxy, halo, C(O)NR₂₃R₂₄, or COOH;
each of R₆, R₈, R₉, R₁₁, R₁₂, R₁₃, and R₁₇, independently, is H or a substituted or unsubstituted moiety selected from C₁-C₆) alkyl, C₁-C₆) alkenyl, thio C₁-C₆) alkyl, cycloalkyl, aryl, and aryl C₁-C₆) alkyl, where said substituent is C₁-C₆) alkyl, halo, hydroxy, C(O)NR₂₅R₂₆, or COOH;
R₁₀ is S, SO, or SO₂;
R₁₈ is COOR₂₇ or C(O)NR₂₈R₂₉, or, together with R₁₆, forms -COOCH₂CH₂-.
R₁₉ is a substituted or unsubstituted moiety selected from C₁-C₆) alkyl, C₁-C₆) alkenyl, aryl, and aryl C₁-C₆) alkyl, where said substituent is C₁-C₆) alkyl, halo, or alkoxy; and
each of R₂₀' R₂₁' R₂₂' R₂₃' R₂₄' R₂₅, R₂₆, R₂₇, R₂₈, and R₂₉, independently, is H or C₁-C₆) alkyl;
provided that if R₂ is (CH₂)_mSH and R₅ is thio C₁-C₆) alkyl, said free thio groups of R₂ and R₅ can form a disulfide bond; or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein said compound has formula I; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1, wherein said compound has formula II; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 2, wherein R₂ is (CH₂)_mSR₂₂, heterocycle, or heterocycle C₁-C₆) alkyl; each of R₄ and R₁₅, independently, is H; R₅ is C₁-C₆) alkyl; R₆ is H; each of R₈, R₉, R₁₁, and R₁₂, independently, is H or C₁-C₆) alkyl; R₁₀ is S; R₁₃ is H; R₁₆ is C₁-C₆) alkyl or substituted thio C₁-C₆) alkyl wherein said substituent is C₁-C₆) alkyl; and R₁₇ is H; or a pharmaceutically acceptable salt thereof.

5. A compound of claim 4, wherein R₁ is NR₂₀R₂₁ and R₂ is (CH₂)_mSR₂₂; or a pharmaceutically acceptable salt thereof.

6. A compound of claim 5, wherein R₃ is CH₂; each of R₈ and R₉, independently, is H; and R₁₈ is COOR₂₇; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 6, wherein R₁ is NH₂; R₂ is CH₂SH ; R₅ is CH(CH₃) (CH₂ CH₃), CH(CH₃)₂, or C(CH₃)₃; each of R₁₁ and R₁₂, independently, is CH₃; R₁₆ is (CH₂)₂SCH₃, (CH₂)₃CH₃, or CH₂CH(CH₃)₂; and R₁₈ is COOH or COOCH₃; or a pharmaceutically acceptable salt thereof.

8. A compound of claim 4, wherein R₁ is H; and R₂ is heterocycle or heterocycle C₁-C₆) alkyl; or a pharmaceutically acceptable salt thereof.

9. A compound of claim 8, wherein R₃ is CH₂; each of R₈ and R₉, independently, is H; and R₁₈ is COOR₂₇; or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9, wherein R₂ is imidazolyl or imidazolyl C₁-C₆) alkyl; R₅ is CH(CH₃)(CH₂CH₃), CH(CH₃)₂, or C(CH₃)₃; each of R₁₁ and R₁₂, independently, is CH₃; R₁₆ is (CH₂)₂SCH₃, (CH₂)₃CH₃, or CH₂CH(CH₃)₂; and R₁₈ is COOH or COOCH₃; or a pharmaceutically acceptable salt thereof.

11. A compound of claim 3, wherein R₂ is (CH₂)_mSR₂₀, heterocycle, or heterocycle C₁-C₆) alkyl; each of R₈, R₉, R₁₁, and R₁₂, independently, is H or C₁-C₆) alkyl; R₁₀ is S; R₁₃ is H; and R₁₅ is H; or a pharmaceutically acceptable salt thereof.

12. A compound of claim 11, wherein R₁ is NR₂₀R₂₁; and R₂ is (CH₂)_mSR₂₂; or a pharmaceutically acceptable salt thereof.

13. A compound of claim 12, wherein R₃ is CH₂; R₈ and R₉ are H; and R₁₉ is substituted or unsubstituted aryl C₁-C₆) alkyl where said substituent is halo or C₁-C₆) alkyl; or a pharmaceutically acceptable salt thereof.

14. A compound of claim 13, wherein R₁ is NH₂; R₂ is CH₂SH; each of R₁₁ and R₁₂, independently, is CH₃; a n d R₁₉ is 2,3-dichlorobenzyl or 1-naphthylmethyl; or a pharmaceutically acceptable salt thereof.

15. A compound of claim 11, wherein R₁ is H and R₂ is heterocycle or heterocycle C₁-C₆) alkyl; or a pharmaceutically acceptable salt thereof.

16. A compound of claim 15, wherein R₃ is CH₂ ; each of R₈ and R₉, independently, is H; and R₁₉ is substituted or unsubstituted aryl C₁-C₆) alkyl where said substituent is halo or C₁-C₆) alkyl; or a pharmaceutically acceptable salt thereof.

17. A compound of claim 16, wherein R₂ is imidazolyl or imidazolyl C₁-C₆) alkyl; each of R₁₁ and R₁₂, independently, is CH₃; and R₁₉ is 2,3-dichlorobenzyl or 1-napthylmethyl; or a pharmaceutically acceptable salt thereof.

18. A compound of claim 1, said compound being of the formula:

19. A compound consisting of a first moiety and a second moiety, wherein each of said first and second moieties, independently, is of formula I or formula II of claim 1 except that each R₂ of said first moiety and R₂ of said second moiety, independently, are -(CH₂)_mS- and form a disulfide bond; or a pharmaceutically acceptable salt thereof.

20. A compound of claim 19 wherein said first and second moieties are identical; or a pharmaceutically acceptable salt thereof.

21. Use of a compound of formula I or formula II

wherein
R₁ i s H or NR₂₀R₂₁;
R₂ is (CH₂)_mSR₂₂, (CH₂)_mSSR₂₂, substituted or unsubstituted heterocycle, or substituted or unsubstituted heterocycle C₁-C₆) alkyl, where m is 1-6 and said substituent is C₁-C₆) alkyl, C₁-C₆) alkenyl, aryl, or aryl C₁-C₆) alkyl;
each of R₃ and R₇, independently, is CH₂ or C(O) ;
each of R₄ and R₁₅, independently, is H or C₁-C₆) alkyl ;
each of R₅ and R₁₆, independently, is H or a substituted or unsubstituted moiety selected from C₁-C₆) alkyl, thio C₁-C₆) alkyl, C₁-C₆) alkenyl, thio C₁-C₆) alkenyl, cycloalkyl, cycloalkyl C₁-C₆) alkyl, aryl, and aryl C₁-C₆) alkyl, where said substituent is C₁-C₆) alkyl, hydroxy, halo, C(O)NR₂₃R₂₄, or COOH;
each of R₆, R₈, R₉, R₁₁, R₁₂, R₁₃, and R₁₇, independently, is H or a substituted or unsubstituted moiety selected from C₁-C₆) alkyl, C₁-C₆) alkenyl, thio C₁-C₆) alkyl, cycloalkyl, aryl, and aryl C₁-C₆) alkyl, where said substituent is C₁-C₆) alkyl, halo, hydroxy, C(O)NR₂₅R₂₆, or COOH;
R₁₀ is S, SO, or SO₂;
R₁₈ is COOR₂₇ or C(O)NR₂₈R₂₉, or, together with R₁₆, forms -COOCH₂CH₂-.
R₁₉ is a substituted or unsubstituted moiety selected from C₁-C₆) alkyl, C₁-C₆) alkenyl, aryl, and aryl C₁-C₆) alkyl, where said substituent is C₁-C₆) alkyl, halo, or alkoxy; and
each of R₂₀' R₂₁' R₂₂' R₂₃' R₂₄' R₂₅, R₂₆, R₂₇, R₂₈, and R₂₉, independently, is H or C₁-C₆) alkyl;
provided that if R₂ is (CH₂)_mSH and R₅ is thio C₁-C₆) alkyl, said free thio groups of R₂ and R₅ can form a disulfide bond; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of tumours or restenosis.

22. Use according to claim 21, wherein the compound has the formula:































or a pharmaceutically acceptable salt thereof.

23. Use according to claim 21, wherein said compound consists of a first moiety and a second moiety, wherein each of said first and second moieties, independently, is of formula:

wherein
R₁ i s H or NR₂₀R₂₁;
each R² of said first moiety and R² of said second moiety, independently are -(CH₂)_mS- and form a disulfide bond; where m is 1-6;
each of R₃ and R₇, independently, is CH₂ or C(O) ;
each of R₄ and R₁₅, independently, is H or (C₁-C₆) alkyl;
each of R₅ and R₁₆, independently, is H or a substituted or unsubstituted moiety selected from (C₁-C₆) alkyl, thio (C₁-C₆) alkyl, (C₂-C₆) alkenyl, thio (C₁-C₆) alkenyl, cycloalkyl, cycloalkyl (C₁-C₆) alkyl, aryl, and aryl (C₁-C₆) alkyl, where said substituent is lower alkyl, hydroxy, halo, C(O)NR₂₃R₂₄, or COOH;
each of R₆, R₈, R₉, R₁₁, R₁₂, R₁₃, and R₁₇, independently, is H or a substituted o r unsubstituted moiety selected from lower alkyl, lower alkenyl, thio lower alkyl, cycloalkyl, aryl, and aryl lower alkyl, where said substituent is lower alkyl, halo, hydroxy, C(O)NR₂₅R₂₆, or COOH;
R₁₀ is S, SO, or SO₂;
R₁₈ is COOR₂₇ or C(O)NR₂₈R₂₉, or, together with R₁₆, forms -COOCH₂CH₂-.
R₁₉ is a substituted or unsubstituted moiety selected from (C₁-C₆) alkyl, (C₂-C₆) alkenyl, aryl, and aryl (C₁-C₆) alkyl, where said substituent is (C₁-C₆) alkyl, halo, or alkoxy; and
each of R₂₀' R₂₁' R₂₃' R₂₄' R₂₅, R₂₆, R₂₇, R₂₈, and R₂₉, independently, is H or (C₁-C₆) alkyl;
provided that if R₂ is (CH₂)_mSH and R₅ is thio (C₁-C₆) alkyl, said free thio groups of R₂ and R₅ can form a disulfide bond; or a pharmaceutically acceptable salt thereof.

Ansprüche

1. Verbindung der Formel I oder Formel II

in denen
R¹ H oder NR₂₀R₂₁ ist,
R² (CH₂)_mSR₂₂, (CH₂)_mSSR₂₂, ein substituierter oder unsubstituierter Heterocyclus oder ein substituierter oder unsubstituierter Heterocyclus-(C₁- bis C₆)-alkyl ist, wobei m 1 bis 6 ist und der Substituent (C₁- bis C₆) -Alkyl, (C₁- bis C₆)-Alkenyl, Aryl oder Aryl-(C₁- bis C₆)-alkyl ist,
jedes von R₃ und R₇ jeweils unabhängig CH₂ oder C(O) ist,
jedes von R₄ und R₁₅ jeweils unabhängig H oder (C₁- bis C₆)-Alkyl ist,
jedes von R₅ und R₁₆ jeweils unabhängig H oder ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, Thio-(C₁- bis C₆)-alkyl, (C₁- bis C₆)-Alkenyl, Thio-(C₁- bis C₆)-alkenyl, Cycloalkyl, Cycloalkyl-(C₁- bis C₆)-alkyl, Aryl und Aryl-(C₁- bis C₆)-alkyl ist, wobei der Substituent (C₁- bis C₆)-Alkyl, Hydroxy, Halogen, C(O)NR₂₃R₂₄ oder COOH ist,
jedes von R₆, R₈, R₉, R₁₁, R₁₂, R₁₃ und R₁₇ jeweils unabhängig H oder ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, (C₁- bis C₆)-Alkenyl, Thio-(C₁- bis C₆)-alkyl, Cycloalkyl, Aryl und Aryl-(C₁- bis C₆)-alkyl ist, wobei der Substituent (C₁- bis C₆) -Alkyl, Halogen, Hydroxy, C(O)NR₂₅R₂₆ oder COOH ist,
R₁₀ S, SO oder SO₂ ist,
R₁₈ COOR₂₇ oder C(O)NR₂₈R₂₉ ist oder zusammen mit R₁₆ COOCH₂CH₂- bildet,
R₁₉ ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, (C₁- bis C₆)-Alkenyl, Aryl und Aryl-(C₁- bis C₆)-alkyl ist, wobei der Substituent (C₁- bis C₆)-Alkyl, Halogen oder Alkoxy ist, und
jedes von R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ und R₂₉ jeweils unabhängig H oder (C₁- bis C₆)-Alkyl ist, mit der Maßgabe, dass wenn R₂ (CH₂)_mSH ist und R₅ Thio-(C₁- bis C₆)-alkyl ist, die freien Thiogruppen von R₂ und R₅ eine Disulfidbindung bilden können, oder ein pharmazeutisch akzeptables Salz derselben.

2. Verbindung nach Anspruch 1, bei der die Verbindung die Formel I aufweist, oder ein pharmazeutisch akzeptables Salz derselben.

3. Verbindung nach Anspruch 1, bei der die Verbindung die Formel II aufweist, oder ein pharmazeutisch akzeptables Salz derselben.

4. Verbindung nach Anspruch 2, bei der R₂ (CH₂)_mSR₂₂, ein Heterocyclus oder ein Heterocyclus-(C₁- bis C₆)-alkyl ist, jedes von R₄ und R₁₅ jeweils unabhängig H ist, R₅ (C₁- bis C₆)-Alkyl ist, R₆ H ist, jedes von R₈, R₉, R₁₁ und R₁₂ jeweils unabhängig H oder (C₁- bis C₆)-Alkyl ist, R₁₀ S ist, R₁₃ H ist, R₁₆ (C₁- bis C₆)-Alkyl oder substituiertes Thio-(C₁- bis C₆)-Alkyl ist, wobei der Substituent (C₁- bis C₆)-Alkyl ist, und R₁₇ H ist, oder ein pharmazeutisch akzeptables Salz derselben.

5. Verbindung nach Anspruch 4, bei der R₁ NR₂₀R₂₁ ist und R₂ (CH₂)_mSR₂₂ ist, oder ein pharmazeutisch akzeptables Salz derselben.

6. Verbindung nach Anspruch 5, bei der R₃ CH₂ ist, jedes von R₈ und R₉ jeweils unabhängig H ist, R₁₈ COOR₂₇ ist, oder ein pharmazeutisch akzeptables Salz derselben.

7. Verbindung nach Anspruch 6, bei der R₁ NH₂ ist, R₂ CH₂SH ist, R₅ CH(CH₃)(CH₂CH₃), CH(CH₃)₂ oder C(CH₃)₃ ist, jedes von R₁₁ und R₁₂ jeweils unabhängig CH₃ ist, R₁₆ (CH₂)₂SCH₃, (CH₂)₃CH₃ oder CH₂CH(CH₃)₂ ist und R₁₈ COOH oder COOCH₃ ist, oder ein pharmazeutisch akzeptables Salz derselben.

8. Verbindung nach Anspruch 4, bei der R₁ H ist, R₂ ein Heterocyclus oder ein Heterocyclus-(C₁- bis C₆)-alkyl ist, oder ein pharmazeutisch akzeptables Salz derselben.

9. Verbindung nach Anspruch 8, bei der R₃ CH₂ ist, jedes von R₈ und R₉ jeweils unabhängig H ist und R₁₈ COOR₂₇ ist, oder ein pharmazeutisch akzeptables Salz derselben.

10. Verbindung nach Anspruch 9, bei der R₂ Imidazolyl oder Imidazolyl-(C₁- bis C₆)-alkyl ist, R₅ CH(CH₃)(CH₂CH₃), CH(CH₃)₂ oder C(CH₃)₃ ist, jedes von R₁₁ und R₁₂ jeweils unabhängig CH₃ ist, R₁₆ (CH₂)₂SCH₃, (CH₂)₃CH₃ oder CH₂CH(CH₃)₂ ist, und R₁₈ COOH oder COOCH₃ ist, oder ein pharmazeutisch akzeptables Salz derselben.

11. Verbindung nach Anspruch 3, bei der R₂ (CH₂)_mSR₂₀, ein Heterocyclus oder ein Heterocyclus-(C₁- bis C₆)-alkyl ist, jedes von R₈ R₉, R₁₁ und R₁₂ jeweils unabhängig H oder (C₁- bis C₆)-Alkyl ist, R₁₀ S, R₁₃ H ist und R₁₅ H ist, oder ein pharmazeutisch akzeptables Salz derselben.

12. Verbindung nach Anspruch 11, bei der R₁ NR₂₀R₂₁ ist und R₂ (CH₂)_mSR₂₂ ist, oder ein pharmazeutisch akzeptables Salz derselben.

13. Verbindung nach Anspruch 12, bei der R₃ CH₂ ist, R₈ und R₉ H sind und R₁₉ substituiertes oder unsubstituiertes Aryl-(C₁- bis C₆)-alkyl ist, wobei der Substituent Halogen oder (C₁- bis C₆)-Alkyl ist, oder ein pharmazeutisch akzeptables Salz derselben.

14. Verbindung nach Anspruch 13, bei der R₁ NH₂ ist, R₂ CH₂SH ist, jedes von R₁₁ und R₁₂ jeweils unabhängig CH₃ ist und R₁₉ 2,3-Dichlorbenzyl oder 1-Naphthylmethyl ist, oder ein pharmazeutisch akzeptables Salz derselben.

15. Verbindung nach Anspruch 11, bei der R₁ H ist und R₂ ein Heterocyclus oder ein Heterocyclus-(C₁- bis C₆)-Alkyl ist, oder ein pharmazeutisch akzeptables Salz derselben.

16. Verbindung nach Anspruch 15, bei der R₃ CH₂ ist, jedes von R₈ und R₉ jeweils unabhängig H ist und R₁₉ substituiertes oder unsubstituiertes Aryl-(C₁- bis C₆)-alkyl ist, wobei der Substituent Halogen oder (C₁- bis C₆)-Alkyl ist, oder ein pharmazeutisch akzeptables Salz derselben.

17. Verbindung nach Anspruch 16, bei der R₂ Imidazolyl oder Imidazolyl-(C₁- bis C₆)-alkyl ist, jedes von R₁₁ und R₁₂ jeweils unabhängig CH₃ ist und R₁₉ 2,3-Dichlorbenzyl oder 1-Naphthylmethyl ist, oder ein pharmazeutisch akzeptables Salz derselben.

18. Verbindung nach Anspruch 1, wobei die Verbindung die Formel































aufweist.

19. Verbindung, die aus einem ersten Anteil und einem zweiten Anteil besteht, wobei jeder von den ersten und zweiten Anteilen jeweils unabhängig die Formel I oder die Formel II gemäß Anspruch 1 aufweist, ausgenommen, dass jedes R₂ des ersten Anteils und R₂ des zweiten Anteils jeweils unabhängig -(CH₂)_mS- sind und eine Disulfidbindung bilden, oder ein pharmazeutisch akzeptables Salz derselben.

20. Verbindung nach Anspruch 19, bei der die ersten und zweiten Anteile identisch sind, oder ein pharmazeutisch akzeptables Salz derselben.

21. Verwendung einer Verbindung der Formel I oder der Formel II

in denen
R¹ H oder NR₂₀R₂₁ ist,
R² (CH₂)_mSR₂₂, (CH₂)_mSSR₂₂, ein substituierter oder unsubstituierter Heterocyclus oder ein substituierter oder unsubstituierter Heterocyclus-(C₁- bis C₆)-alkyl ist, wobei m 1 bis 6 ist und der Substituent (C₁- bis C₆) -Alkyl, (C₁- bis C₆)-Alkenyl, Aryl oder Aryl-(C₁- bis C₆)-alkyl ist,
jedes von R₃ und R₇ jeweils unabhängig CH₂ oder C(O) ist,
jedes von R₄ und R₁₅ jeweils unabhängig H oder (C₁- bis C₆)-Alkyl ist,
jedes von R₅ und R₁₆ jeweils unabhängig H oder ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, Thio-(C₁- bis C₆)-alkyl, (C₁- bis C₆) - Alkenyl, Thio-(C₁- bis C₆)-alkenyl, Cycloalkyl, Cycloalkyl-(C₁- bis C₆)-alkyl, Aryl und Aryl- (C₁- bis C₆) -alkyl ist, wobei der Substituent (C₁- bis C₆)-Alkyl, Hydroxy, Halogen, C(O)NR₂₃R₂₄ oder COOH ist,
jedes von R₆, R₈, R₉, R₁₁, R₁₂, R₁₃ und R₁₇ jeweils unabhängig H oder ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, (C₁- bis C₆)-Alkenyl, Thio-(C₁- bis C₆)-alkyl, Cycloalkyl, Aryl und Aryl-(C₁- bis C₆)-alkyl ist, wobei der Substituent (C₁- bis C₆)-Alkyl, Halogen, Hydroxy, C(O)NR₂₅R₂₆ oder COOH ist,
R₁₀ S, SO oder SO₂ ist,
R₁₈ COOR₂₇ oder C(O)NR₂₈R₂₉ ist oder zusammen mit R₁₆ COOCH₂CH₂- bildet,
R₁₉ ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, (C₁- bis C₆)-Alkenyl, Aryl und Aryl-(C₁- bis C₆)-alkyl ist, wobei der Substituent (C₁- bis C₆)-Alkyl, Halogen oder Alkoxy ist, und
jedes von R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ und R₂₉ jeweils unabhängig H oder (C₁- bis C₆)-Alkyl ist, mit der Maßgabe, dass wenn R₂ (CH₂)_mSH ist und R₅ Thio-(C₁- bis C₆)-alkyl ist, die freien Thiogruppen von R₂ und R₅ eine Disulfidbindung bilden können, oder ein pharmazeutisch akzeptables Salz derselben, bei der Herstellung eines Medikaments für die Behandlung von Tumoren oder Restenose.

22. Verwendung nach Anspruch 21, bei der die Verbindung die Formel































aufweist, oder ein pharmazeutisch akzeptables Salz derselben.

23. Verwendung nach Anspruch 21, bei der die Verbindung aus einem ersten Anteil und einem zweiten Anteil besteht, wobei jeder der ersten und zweiten Anteile jeweils unabhängig die Formel

aufweist, in denen
R¹ H oder NR₂₀R₂₁ ist,
jedes R² des ersten Anteils and R² des zweiten Anteils jeweils unabhängig -(CH₂)_mS- sind und eine Disulfidbindung bilden, wobei m 1 bis 6 ist,
jedes von R₃ und R₇ jeweils unabhängig CH₂ oder C(O) ist,
jedes von R₄ und R₁₅ jeweils unabhängig H oder (C₁- bis C₆) -Alkyl ist,
jedes von R₅ und R₁₆ jeweils unabhängig H oder ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, Thio-(C₁- bis C₆)-Alkyl, (C₂- bis C₆)-Alkenyl, Thio-(C₁- bis C₆)-Alkenyl, Cycloalkyl, Cycloalkyl-(C₁- bis C₆)-Alkyl, Aryl und Aryl-(C₁- bis C₆)-Alkyl ist, wobei der Substituent niederes Alkyl, Hydroxy, Halogen, C (O) NR₂₃R₂₄ oder COOH ist,
jedes von R₆, R₈, R₉, R₁₁, R₁₂, R₁₃ und R₁₇ jeweils unabhängig H oder ein substituierter oder unsubstituierter Anteil ausgewählt aus niederes Alkyl, niederes Alkenyl, Thioniederes alkyl, Cycloalkyl, Aryl und Aryl-niederes alkyl ist, wobei der Substituent niederes Alkyl, Halogen, Hydroxy, C(O)NR₂₅R₂₆ oder COOH ist,
R₁₀ S, SO oder SO₂ ist,
R₁₈ COOR₂₇ oder C (O) NR₂₈R₂₉ ist oder zusammen mit R₁₆ COOCH₂CH₂- bildet,
R₁₉ ein substituierter oder unsubstituierter Anteil ausgewählt aus (C₁- bis C₆)-Alkyl, (C₂- bis C₆)-Alkenyl, Aryl und Aryl-(C₁- bis C₆)-Alkyl ist, wobei der Substituent (C₁- bis C₆)-Alkyl, Halogen oder Alkoxy ist, und
jedes von R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ und R₂₉ jeweils unabhängig H oder (C₁- bis C₆)-Alkyl ist, mit der Maßgabe, dass wenn R₂ (CH₂)_mSH ist und R₅ Thio-(C₁- bis C₆)-Alkyl ist, die freien Thiogruppen von R₂ und R₅ eine Disulfidbindung bilden können, oder ein pharmazeutisch akzeptables Salze derselben.

Revendications

1. Composé de formule I ou de formule II :

où

- R₁ représente H ou NR₂₀R₂₁ ;

- R₂ représente (CH₂)_mSR₂₂, (CH₂)_mSSR₂₂, hétérocycle substitué ou non substitué, ou hétérocycle alkyle en C₁-C₆ substitué ou non substitué, où m vaut 1-6 et ledit substituant est alkyle en C₁-C₆, alcényle en C₁-C₆, aryle ou aryl alkyle en C₁-C₆;

- R₃ et R₇ représentent chacun indépendamment CH₂ ou C(O) ;

- R₄ et R₁₅ représentent chacun indépendamment H ou alkyle en C₁-C₆ ;

- R₅ et R₁₆ représentent chacun indépendamment H ou une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, thio alkyle en C₁-C₆, alcényle en C₁-C₆, thio alcényle en C₁-C₆, cycloalkyle, cycloalkyl alkyle en C₁-C₆, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyle en C₁-C₆, hydroxy, halo, C(O)NR₂₃R₂₄ ou COOH ;

- R₆, R₈, R₉, R₁₁, R₁₂, R₁₃ et R₁₇ représentent chacun indépendamment H ou une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, alcényle en C₁-C₆, thio alkyle en C₁-C₆, cycloalkyle, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyle en C₁-C₆, halo, hydroxy, C(O)NR₂₅R₂₆ ou COOH ;

- R₁₀ représente S, SO ou SO₂ ;

- R₁₈ représente COOR₂₇ ou C(O)NR₂₈R₂₉, ou, conjointement avec R₁₆, forme -COOCH₂CH₂-.

- R₁₉ est une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, alcényle en C₁-C₆, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyle en C₁-C₆, halo ou alcoxy ; et

- R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ et R₂₉ représentent chacun indépendamment H ou alkyle en C₁-C₆;

à la condition que, si R₂ représente (CH₂)_mSH et R₅ représente thio alkyle en C₁-C₆, lesdits groupes thio libres de R₂ et R₅ peuvent former une liaison disulfure ;
ou un sel pharmaceutiquement acceptable de celui-ci.

2. Composé selon la revendication 1, dans lequel ledit composé a la formule I ; ou un sel pharmaceutiquement acceptable de celui-ci.

3. Composé selon la revendication 1, dans lequel ledit composé a la formule II ; ou un sel pharmaceutiquement acceptable de celui-ci.

4. Composé selon la revendication 2, dans lequel R₂ représente (CH₂)_mSR₂₂, hétérocycle ou hétérocycle alkyle en C₁-C₆; R₄ et R₁₅ représentent chacun indépendamment H ; R₅ représente alkyle en C₁-C₆; R₆ représente H ; R₈, R₉, R₁₁ et R₁₂ représentent chacun indépendamment H ou alkyle en C₁-C₆; R₁₀ représente S ; R₁₃ représente H ; R₁₆ représente alkyle en C₁-C₆ ou thio alkyle en C₁-C₆ substitué dans lequel ledit substituant est alkyle en C₁-C₆; et R₁₇ représente H ;
ou un sel pharmaceutiquement acceptable de celui-ci.

5. Composé selon la revendication 4, dans lequel R₁ représente NR₂₀R₂₁ et R₂ représente (CH₂)_mSR₂₂ ; ou un sel pharmaceutiquement acceptable de celui-ci.

6. Composé selon la revendication 5, dans lequel R₃ représente CH₂ ; R₈ et R₉ représentent chacun indépendamment H ; et R₁₈ représente COOR₂₇ ; ou un sel pharmaceutiquement acceptable de celui-ci.

7. Composé selon la revendication 6, dans lequel R₁ représente NH₂ ; R₂ représente CH₂SH ; R₅ représente CH(CH₃) (CH₂ CH₃), CH(CH₃)₂ ou C(CH₃)₃ ; R₁₁ et R₁₂ représentent chacun indépendamment CH₃ ; R₁₆ représente (CH₂)₂SCH₃, (CH₂)₃CH₃ ou CH₂CH(CH₃)₂ ; et R₁₈ représente COOH ou COOCH₃ ; ou un sel pharmaceutiquement acceptable de celui-ci.

8. Composé selon la revendication 4, dans lequel R₁ représente H ; et R₂ représente hétérocycle ou hétérocycle alkyle en C₁-C₆; ou un sel pharmaceutiquement acceptable de celui-ci.

9. Composé selon la revendication 8, dans lequel R₃ représente CH₂ ; R₈ et R₉ représentent chacun indépendamment H ; et R₁₈ représente COOR₂₇ ; ou un sel pharmaceutiquement acceptable de celui-ci.

10. Composé selon la revendication 9, dans lequel R₂ représente imidazolyle ou imidazolyl alkyle en C₁-C₆; R₅ représente CH(CH₃) (CH₂CH₃), CH(CH₃)₂ ou C(CH₃)₃ ; R₁₁ et R₁₂ représentent chacun indépendamment CH₃ ; R₁₆ représente (CH₂)₂SCH₃, (CH₂)₃CH₃ ou CH₂CH(CH₃)₂ ; et R₁₈ représente COOH ou COOCH₃ ; ou un sel pharmaceutiquement acceptable de celui-ci.

11. Composé selon la revendication 3, dans lequel R₂ représente (CH₂)_mSR₂₀, hétérocycle ou hétérocycle alkyle en C₁-C₆; R₈, R₉, R₁₁ et R₁₂ représentent chacun indépendamment H ou alkyle en C₁-C₆; R₁₀ représente S ; R₁₃ représente H ; et R₁₅ représente H ; ou un sel pharmaceutiquement acceptable de celui-ci.

12. Composé selon la revendication 11, dans lequel R₁ représente NR₂₀R₂₁ ; et R₂ représente (CH₂)_mSR₂₂ ; ou un sel pharmaceutiquement acceptable de celui-ci.

13. Composé selon la revendication 12, dans lequel R₃ représente CH₂ ; R₈ et R₉ représentent H ; et R₁₉ représente aryl alkyle en C₁-C₆ substitué ou non substitué, où ledit substituant est halo ou alkyle en C₁-C₆ ; ou un sel pharmaceutiquement acceptable de celui-ci.

14. Composé selon la revendication 13, dans lequel R₁ représente NH₂ ; R₂ représente CH₂SH ; R₁₁ et R₁₂ représentent chacun indépendamment CH₃ ; et R₁₉ représente 2,3-dichlorobenzyle ou 1-naphtylméthyle ; ou un sel pharmaceutiquement acceptable de celui-ci.

15. Composé selon la revendication 11, dans lequel R₁ représente H et R₂ représente hétérocycle ou hétérocycle alkyle en C₁-C₆; ou un sel pharmaceutiquement acceptable de celui-ci.

16. Composé selon la revendication 15, dans lequel R₃ représentent CH₂; R₈ et R₉ représentent chacun indépendamment H ; et R₁₉ représente aryl alkyle en C₁-C₆ substitué ou non substitué, où ledit substituant est halo ou alkyle en C₁-C₆; ou un sel pharmaceutiquement acceptable de celui-ci.

17. Composé selon la revendication 16, dans lequel R₂ représente imidazolyle ou imidazolyl alkyle en C₁-C₆; R₁₁ et R₁₂ représentent chacun indépendamment CH₃ ; et R₁₉ représente 2,3-dichlorobenzyle ou 1-naphtylméthyle ; ou un sel pharmaceutiquement acceptable de celui-ci.

18. Composé selon la revendication 1, ledit composé étant de la formule :

19. Composé consistant en une première fraction et une seconde fraction, dans lequel lesdites première et seconde fractions sont chacune indépendamment de la formule I ou de la formule II de la revendication 1, excepté que R₂ de ladite première fraction et R₂ de ladite seconde fraction représentent chacun indépendamment -(CH₂)_mS- et forment une liaison disulfure ; ou un sel pharmaceutiquement acceptable de celui-ci.

20. Composé selon la revendication 19, dans lequel lesdites première et seconde fractions sont identiques ; ou un sel pharmaceutiquement acceptable de celui-ci.

21. Utilisation d'un composé de la formule I ou de la formule II :

où

- R₁ représente H ou NR₂₀R₂₁ ;

- R₂ représente (CH₂)_mSR₂₂, (CH₂)_mSSR₂₂, hétérocycle substitué ou non substitué, ou hétérocycle alkyle en C₁-C₆ substitué ou non substitué, où m vaut 1-6 et ledit substituant est alkyle en C₁-C₆, alcényle en C₁-C₆, aryle ou aryl alkyle en C₁-C₆;

- R₃ et R₇ représentent chacun indépendamment CH₂ ou C(O) ;

- R₄ et R₁₅ représentent chacun indépendamment H ou alkyle en C₁-C₆;

- R₅ et R₁₆ représentent chacun indépendamment H ou une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, thio alkyle en C₁-C₆, alcényle en C₁-C₆, thio alcényle en C₁-C₆, cycloalkyle, cycloalkyl alkyle en C₁-C₆, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyle en C₁-C₆, hydroxy, halo, C(O)NR₂₃R₂₄ ou COOH ;

- R₆, Re, R₉, R₁₁, R₁₂, R₁₃ et R₁₇ représentent chacun indépendamment H ou une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, alcényle en C₁-C₆, thio alkyle en C₁-C₆, cycloalkyle, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyle en C₁-C₆, halo, hydroxy, C(O)NR₂₅R₂₆ ou COOH ;

- R₁₀ représente S, SO ou SO₂ ;

- R₁₈ représente COOR₂₇ ou C(O)NR₂₈R₂₉, ou, conjointement avec R₁₆, forme -COOCH₂CH₂- ;

- R₁₉ est une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, alcényle en C₁-C₆, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyle en C₁-C₆, halo ou alcoxy ; et

- R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ et R₂₉ représentent chacun indépendamment H ou alkyle en C₁-C₆;

à la condition que, si R₂ représente (CH₂)_mSH et R₅ représente thio alkyle en C₁-C₆, lesdits groupes thio libres de R₂ et R₅ peuvent former une liaison disulfure ;
ou d'un sel pharmaceutiquement acceptable de celui-ci, dans la fabrication d'un médicament pour le traitement de tumeurs ou d'une resténose.

22. Utilisation selon la revendication 21, dans laquelle le composé a la formule :































ou d'un sel pharmaceutiquement acceptable de celui-ci.

23. Utilisation selon la revendication 21, dans laquelle ledit composé consiste en une première fraction et une seconde fraction, dans laquelle les dites première et seconde fractions sont chacune indépendamment de la formule:

où

- R₁ représente H ou NR₂₀R₂₁ ;

- chaque R₂ de ladite première fraction et R₂ de ladite seconde fraction indépendamment représentent -(CH₂)_mS- et forment une liaison disulfure, où m vaut 1-6 ;

- R₃ et R₇ représentent chacun indépendamment CH₂ ou C(O) ;

- R₄ et R₁₅ représentent chacun indépendamment H ou alkyle en C₁-C₆ ;

- R₅ et R₁₆ représentent chacun indépendamment H ou une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, thio alkyle en C₁-C₆, alcényle en C₁-C₆, thio alcényle en C₁-C₆, cycloalkyle, cycloalkyl alkyle en C₁-C₆, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyl inférieur, hydroxy, halo, C(O)NR₂₃R₂₄ ou COOH ;

- R₆, R₈, R₉, R₁₁, R₁₂, R₁₃ et R₁₇ représentent chacun indépendamment H ou une fraction substituée ou non substituée choisie parmi alkyle inférieur, alcényle inférieur, thio alkyle inférieur, cycloalkyle, aryle et aryl alkyle inférieur, où ledit substituant est alkyle inférieur, halo, hydroxy, C(O)NR₂₅R₂₆ ou COOH ;

- R₁₀ représente S, SO ou SO₂ ;

- R₁₈ représente COOR₂₇ ou C(O)NR₂₈R₂₉, ou, conjointement avec R₁₆, forme -COOCH₂CH₂- ;

- R₁₉ est une fraction substituée ou non substituée choisie parmi alkyle en C₁-C₆, alcényle en C₁-C₆, aryle et aryl alkyle en C₁-C₆, où ledit substituant est alkyle en C₁-C₆, halo ou alcoxy ; et

- R₂₀, R₂₁, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ et R₂₉ représentent chacun indépendamment H ou alkyle en C₁-C₆;

à la condition que, si R₂ représente (CH₂)_mSH et R₅ représente thio alkyle en C₁-C₆, lesdits groupes thio libres de R₂ et R₅ peuvent former une liaison disulfure ;
ou un sel pharmaceutiquement acceptable de celui-ci.